A FcγRIII-engaging bispecific antibody expands the range of HER2-expressing breast tumors eligible to antibody therapy
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Marc Turini1,2,3,4, Patrick Chames1,2,3,4, Pierre Bruhns5,6, Daniel Baty1,2,3,4,* and Brigitte Kerfelec1,2,3,4,*
1 INSERM, U1068, CRCM, Marseille, France
2 Institut Paoli-Calmettes, Marseille, France
3 Aix-Marseille Université, UM105, Marseille, France
4 CNRS, UMR7258, CRCM, Marseille, France
5 Département d’Immunologie, Laboratoire Anticorps en Thérapie et Pathologie, Institut Pasteur, Paris, France
6 INSERM, U760, Paris, France
* Senior co-authors
Brigitte Kerfelec, email:
Keywords: bispecific antibody, breast cancer, FcγRIIIA polymorphism, HER2, trastuzumab
Received: March 20, 2014 Accepted: June 10, 2014 Published: June 11, 2014
Trastuzumab is established as treatment of HER2high metastatic breast cancers but many limitations impair its efficacy. Here, we report the design of a Fab-like bispecific antibody (HER2bsFab) that displays a moderate affinity for HER2 and a unique, specific and high affinity for FcγRIII. In vitro characterization showed that ADCC was the major mechanism of action of HER2bsFab as no significant HER2-driven effect was observed. HER2bsFab mediated ADCC at picomolar concentration against HER2high, HER2low as well as trastuzumab-refractive cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth by recruitment of mouse FcγRIII and IV-positive resident effector cells and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2low tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of V/F158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Thus, taking advantage of its epitope specificity and affinity for HER2 and FcγRIIIA, HER2bsFab exhibits potent anti-tumor activity against HER2low tumors while evading most of trastuzumab Fc-linked limitations thereby potentially enlarging the number of patients eligible for breast cancer immunotherapy.
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